The invention relates to blood cleansing systems in general and, more particularly, to a blood cleansing modality commonly referred to as hemodiafiltration.
Hemodiafiltration combines both standard dialysis and hemofiltration into one process, whereby a dialyzer cartridge containing a high flux membrane is used to remove substances from the blood both by diffusion and by convection. The removal of substances by diffusion is accomplished by establishing a concentration gradient across a semipermeable membrane by flowing a dialysate solution on one side of the membrane while simultaneously flowing blood on the opposite side of the membrane. In existing systems, to enhance removal of substances using hemodiafiltration, a solution called substitution fluid is continuously added to the blood either prior to the dialyzer cartridge (pre-dilution) or after the dialyzer cartridge (post-dilution). An amount of fluid equal to that of the added substitution fluid is ultrafiltered across the dialyzer cartridge membrane carrying with it additional solutes.
Substitution fluid is usually purchased as a sterile/non-pyrogenic fluid contained in large flexible bags or is produced on-line by filtration of a non-sterile dialysate through a suitable filter cartridge rendering it sterile and non-pyrogenic Techniques for online production of substitution fluid have been described in the literature, for example, in D. Limido et al., xe2x80x9cClinical Evaluation of AK-100 ULTRA for Predilution HF with On-Line Prepared Bicarbonate Substitution Fluid. Comparison with HD and Acetate Postdilution HFxe2x80x9d, International Journal of Artificial Organs, Vol. 20, No. 3 (1997), pp. 153-157.
In general, existing hemodiafiltration schemes use a single dialyzer cartridge containing a high flux semi-permeable membrane, for example see P. Ahrenholz et al., xe2x80x9cOn-Line Hemodiafiltration with Pre- and Postdilution: A Comparison of Efficiencyxe2x80x9d, International Journal of Artificial Organs, Vol. 20, No. 2 (1997), pp. 81-90. In prior art systems, substitution fluid is introduced into the blood stream either in a pre-dilution mode or in a post-dilution mode relative to the dialyzer cartridge. The preferred mode for maximal removal of both small and large substances from blood, in accordance with the prior art, is the post-dilutional mode because this mode achieves the highest concentration gradient between the blood and the dialysate fluid. In a typical pre-dilution mode with on-line generation of substitution fluid, however, the bloodside concentration is lowered relative to the dialysate fluid. As a result, removal (or clearance) of substances can decrease, as described in The International Journal of Artificial Organs, vol. 20, pp. 81-90. This decrease is particularly apparent for smaller molecules, like urea, where mass transport is driven more by diffusion than by convection. Use of two dialyzer cartridges in a hemodiafiltration scheme has been reported in J. H. Miller et al., xe2x80x9cTechnical Aspects of High-Flux Hemodiafiltration for Adequate Short (Under 2 Hours) Treatmentxe2x80x9d, Transactions of the American Society Artificial Internal Organs (1984), pp. 377-380. In this scheme, the substitution fluid is reverse-filtered through the membrane of the first dialyzer cartridge. A variation of this method is described in B. Nederlof, xe2x80x9cHEMO(DIA)FILTRATION APPARATUS AND FILTRATE FLOW REGULATORxe2x80x9d, U.S. Pat. No. 5,660,722 (1997), where a dialysate pump between the dialyzers is used to regulate the amount of reverse-filtration in the second dialyzer cartridge.
Certain trade-offs exist with respect to removal of different size molecules when comparing pre-dilution diafiltration and post-dilution diafiltration using a single dialyzer cartridge. For example, on-line pre-dilution diafiltration schemes generally achieve higher convection filtration rates, compared to on-line post-dilution diafiltration, enhancing removal of large molecules; however, the increased removal by convection comes at the expense of reducing the removal of small molecules, such as urea and creatinine. In on-line post-dilution diafiltration schemes, on the other hand, the amount of fluid that may be filtered from the blood as it passes through the dialyzer cartridge is limited. Specifically, the filterable amount is dependent upon several factors, which include blood flow rate, blood hematocrit, and blood protein concentration. Typically, the filterable amount is 20% to 30% of the incoming blood flow rate. For example, at a blood flow rate of 300 milliliter per minute (ml/min), the filterable amount is typically limited to 90 ml/min. In the two dialyzer approach, the filterable amount is also limited to about 20% to 30% of the blood flow because forward filtration occurs only in the first dialyzer. The second dialyzer then re-infuses the fluid lost in the first dialyzer by reverse-filtration, as in on-line post-dilution diafiltration.
This invention seeks to provide a hemodiafiltration method and apparatus that overcomes the convection limitation associated with on-line post-dilution diafiltration schemes using a single dialyzer cartridge, as well as the loss of small molecule clearance associated with on-line pre-dilution diafiltration schemes using a single dialyzer cartridge.
It is an object of the present invention to provide an improved method of hemodiafiltration using two dialyzer cartridges or a single cartridge having two dialyzer stages. In addition, the present invention provides methods and systems for regulating the amount of ultrafiltration in each of the two dialyzers. It will be understood by persons of ordinary skill in the art that, although the invention is described herein in the context of hemodiafiltration using substitution fluid which is produced xe2x80x9con-linexe2x80x9d, the hemodiafiltration methods and systems of the invention can be readily modified to be used in conjunction with other sources of substitution fluid.
According to an aspect of the invention, a hemodiafiltration system includes at least two dialyzer cartridges, or a single cartridge with at least two dialyzer stages, which perform diafiltration, and at least one sterility filter which converts dialysate fluid into a sterile substitution fluid, preferably on-line. Additional components (e.g. pumps, check valves, mixing chambers, control units) may also be used in conjunction with the invention, as described below.
Each dialyzer contains a semi-permeable membrane that is embedded within a jacket or housing. The semi-permeable membrane separates the device into a blood compartment and a dialysate compartment. At least two dialyzer cartridges are used to carry out the diafiltration process in accordance with the invention. Alternatively, the two dialyzer cartridges may be combined into a single cartridge including two dialyzer sections. The at least one sterility filter cartridge preferably also contains a semi-permeable membrane. This filter is used to remove bacteria, endotoxins, and other particulate from dialysate in order to generate a suitable substitution fluid stream, preferably on-line.
During operation of the system, blood enters the bloodside compartment of the first dialyzer cartridge, wherein a portion of plasma water is filtered across the semi-permeable membrane into the adjacent dialysate compartment. Upon exiting the first dialyzer cartridge, substitution fluid is added back to the blood at a rate higher than the rate at which fluid is filtered out of the blood in the first dialyzer cartridge. The diluted blood then enters the bloodside compartment of the second dialyzer cartridge, wherein additional plasma water is filtered across the semi-permeable membrane into the adjacent dialysate compartment at a rate substantially equal to the difference between the rate at which substitution fluid is added to the blood upon exiting the first dialyzer cartridge and the filtration rate at the first dialyzer. Thus, the substitution fluid acts as a post-dilution fluid relative to the first dialyzer cartridge as well as a pre-dilution fluid relative to the second dialyzer cartridge. The advantage of operating the system in this mode is that the loss of small molecular weight clearance due to the diluted fluid entering the second dialyzer cartridge is compensated by a gain in small molecular weight clearance in the first dialyzer cartridge. Clearance of larger molecular weight substances is further enhanced because the total filtration of plasma water can be effectively increased (e.g., 40% to 100% of the incoming blood flow rate) compared to that of a single dialyzer cartridge operating in a post-dilution mode or two dialyzers in series with the second dialyzer being operated in a reverse-filtration mode.
Dialysate fluid for the system of the invention may be generated using existing methods. The dialysate fluid enters the second dialyzer cartridge and flows counter-current with respect to the blood flow direction. The dialysate fluid acts to set-up a concentration gradient against the bloodside fluid, thereby inducing diffusion of solutes across the semi-permeable membrane. As the dialysate traverses through the dialysate compartment, the dialysate flow rate increases due to plasma water being filtered across into the dialysate compartment as described above. Upon exiting the second dialyzer, the dialysate fluid enters the first dialyzer cartridge, flowing counter-current with respect to the bloodside fluid. The dialysate flow rate increases as the dialysate flows through the dialysate compartment, due to filtration of plasma water across the semi-permeable membrane. Upon exiting the dialyzer cartridge, the spent or used dialysate is transported back to the dialysis machine. By including additional components, for example, an inter-stage pump located either in the dialysate path between the two dialyzers or in the blood path between the two dialyzers, it is possible to regulate the amount of plasma water filtered across the membranes of the respective cartridges. This improved control enables the system to achieve even higher effective substitution rates.
Preparation of the sterile/non-pyrogenic substitution fluid may be accomplished by drawing a portion of fresh dialysate solution from a fresh dialysate inlet line and passing it through at least one sterile filter cartridge prior to introducing it into the blood between the two dialyzer stages. In the present invention, the dialysis machine generally performs all of its normal functions, such as preparing dialysate, metering dialysate flow rate, balancing flow, monitoring pressures, ultrafiltration control, monitoring spent dialysate for presence of blood etc.
The present invention may be implemented in a number of ways. In one embodiment, substitution fluid is added to the blood between the two dialyzer stages without additional components to regulate the filtration in each stage. In a second and third embodiment, an inter-stage dialysate pump is added as a means for controlling the relative filtration rates of the two dialyzer stages. In the second embodiment, a feedback control loop based on pressure inputs is used as means for balancing the transmembrane pressure (TMP) of each dialyzer. In the third embodiment, a feedback control loop based on a measured inter-stage flow rate is used. In a fourth embodiment, a positive displacement pump is used as an inter-stage dialysate pump, and a feed forward control loop is used to regulate the relative filtration rates of the two dialyzers. In a fifth embodiment, a check valve is used to shunt the flow past the inter-stage dialysate pump. The advantage of this last embodiment is that the check valve simplifies the control loop for operating the inter-stage dialysate pump. A sixth and seventh embodiment of the invention are generally similar to the fourth and fifth embodiments, respectively, except for the fact that an inter-stage blood pump is used instead of an inter-stage dialysate pump. Finally, in an eighth embodiment of the invention, the inter-stage pump is controlled by a feedback loop based on measurement of inter-stage blood hematocrit.